marijuana: clearing the smoke on clinical and policy issues · 2018-07-23 · disorder for...

Yale School of Medicine, Section of General Internal Medicine

Marijuana: Clearing the Smoke on Clinical and Policy Issues

Jeanette M. Tetrault, MD FACP FASAMAssociate Professor of Medicine

Program Director, Addiction Medicine FellowshipYale University School of Medicine


Learning objectives

• Define the key components of marijuana as a substance and review relevant epidemiology and terminology

• Explore US policy regarding MJ decriminalization to legalization

• Summarize adverse health effects and other potential risks of marijuana use

• Examine the tension between health risks of marijuana vs. marijuana as medicine


What is marijuana?

• Dried flowers, leaves, stems and seeds of the Cannabis sativa plant

• Usually smoked as a cigarette or in a pipe; can be orally ingested

• Potency related to concentration of Δ9-tetrahydrocannabinol(THC) and route of administration


Δ9-TETRAHYDROCANNABINOL (THC)

• Psychoactive ingredient in Cannabis sativa

• Synthetic form is active ingredient of dronabinol (Marinol), approved in 1985 for intractable nausea

• 70+ other cannabinoids, many of which are present to varying degrees in a single C. sativa plant; some non-THC cannabinoids may have medical use

Δ9-THC


Marijuana use among individuals age 17 or older

NSDUH 2013


Why the increase?


Cannabis Use Disorder DSM 5

A problematic pattern of cannabis use leading to clinically significant impairment or distress, as manifested by two or more of the following within a 12-month period:

• Cannabis is often taken in larger amounts or over a longer period than was intended

• There is a persistent desire or unsuccessful efforts to cut down or control cannabis use

• A great deal of time is spent in activities necessary to obtain cannabis, use cannabis, or recover from its effects

• Craving, or a strong desire or urge to use cannabis


Cannabis Use Disorder, Cont’d

• Recurrent cannabis use resulting in a failure to fulfill major role obligations at work, school, or home

• Continued cannabis use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of cannabis

• Important social, occupational, or recreational activities are given up or reduced because of cannabis use

• Recurrent cannabis use in situations in which it is physically hazardous

• Continued cannabis use despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by use

• Tolerance

• Withdrawal


Cannabis withdrawal: New to DSM 5

• Cessation of cannabis use that has been heavy and prolonged

• Three or more of the following signs and symptoms develop within approximately one week after the cannabis cessation:– Irritability, anger, or aggression– Nervousness or anxiety– Sleep difficulty (eg, insomnia, disturbing dreams)– Decreased appetite or weight loss– Restlessness– Depressed mood– At least one of the following physical symptoms causing significant discomfort:

abdominal pain, shakiness/tremors, sweating, fever, chills, or headache

• Cause distress or impairment

• No other explanation for symptoms

Of note, symptoms generally resolve in 7-14 days but may persist for weeks


US Love-Hate Relationship

Reefer Madness, 1936

“ A cautionary tale about the ill effects of marijuana … a trio of drug dealers try to corrupt innocent teenagers with wild parties and jazz music.”

Fast Times at Ridgemont High, 1982…

Jeff Spicoli


US Love-Hate Relationship

Reefer Madness, 1936

“ A cautionary tale about the ill effects of marijuana … a trio of drug dealers try to corrupt innocent teenagers with wild parties and jazz music.”

Harold and Kumar Go To White Castle2004


Policy timeline• 1970: Controlled Substances Act passed by Congress, marijuana listed as schedule I drug

• 1985: dronabinol (synthetic THC) approved in the US for treatment of intractable nausea

• 1996-2018: 29 states + PR, Guam medical marijuana, 9 states & D.C. legalize recreational use

• 2005: Supreme Court decision (Gonzales v. Raich)

– Federal law enforcement has the authority to arrest and prosecute MDs or patients

• 2009, 2014: Department of Justice Memorandum

– Federal resources should not be used to prosecute those who comply with states laws

• 2008-2010: IOM, ACP, AMA

– Petitioned DEA/FDA to reschedule marijuana to schedule II …it remains schedule I to this day

• 2018: AG Sessions rescinds Obama-era memoranda

• 4/20/18: Schumer (D, NY)- Introduces bill to decriminalize marijuana


Moderate acute effects

• Acute marijuana intoxication

– agitation, psychosis, and anxiety

– tachycardia and hypertension

• Cannabinoid Hyperemesis Syndrome

• Pediatric Exposures

Kim &Monte Annals of Em Med 2016https://www.greenrushdaily.com/2016/08/17/cannabinoid-hyperemesis-syndrome-cannabis/

Yale School of Medicine, Section of General Internal Medicine Volkow ND et al. NEJM 2014;370:2219-2227.

Adverse effects of marijuana use


• 16 person committee reviewed > 10,000 abstracts published since 1999

• Focused on recently published systematic reviews and high quality primary research for 11 groups of health effects including both harms and therapeutic effects

Report of National Academies of Science, Engineering and Medicine. Health Effects of Cannabis and Cannabinoids. 2017


Cumulative Probability of Transitioning to Substance Use Disorder for Nicotine, Alcohol, Marijuana and Cocaine

16

Lopez-Quintero, C. et al. Drug & Alcohol Dependence 2011

Addiction to MJ:9% of overall,

17% if begin during adolescence,

25-50% of daily users


Health effects of cannabis and cannabinoids: SUD

There is substantial evidence that:

• Initiating cannabis use at an earlier age is a risk factor for the development of problem cannabis use

There is moderate evidence of a statistical association between cannabis use and:

• The development of substance use disorder for substances, including alcohol, tobacco, and other illicit drugs



Adolescent vulnerability in IQ decline

Meier M H et al. PNAS 2012


Health effects of cannabis and cannabinoids: Psychosocial domains


• The impairment in the cognitive domains of learning, memory, and attention



Association between mental health conditions and MJ use

Blanco et al JAMA Psychiatry, 2016


Health effects of cannabis and cannabinoids: Mental Health

There is substantial evidence of a statistical association between cannabis use and:

• The development of schizophrenia or other psychoses, with the highest risk among the most frequent users


• Increased symptoms of mania and hypomania in individuals diagnosed with bipolar disorders (regular cannabis use)

• A small increased risk for the development of depressive disorders

• Increased incidence of suicidal ideation and suicide attempts with a higher incidence among heavier users

• Increased incidence of suicide completion

• Increased incidence of social anxiety disorder (regular cannabis use)

• Major depressive disorder is a risk factor for the development of problem cannabis use



Pulmonary effects of smoked marijuana

• Acute bronchodilation (FEV1 increase ~ 0.15-0.25L)

• Long-term cough (OR 2.0, 95% CI 1.32-3.01), phlegm, wheeze; however data were inconclusive regarding an association between long-term marijuana smoking and airflow obstruction(1)

• At low levels of exposure, FEV1 increased by 13 mL/joint-year and FVC by 20 mL/joint-year, but at higher levels of exposure, airflow obstruction was observed(2)

1. Tetrault JM et al. Archives IM 2007

2. Pletcher MJ et al. JAMA 2012


Health effects of cannabis and cannabinoids: Respiratory disease

There is substantial evidence of a statistical association between cannabis smoking and:

• Worse respiratory symptoms and more frequent chronic bronchitis episodes (long-term cannabis smoking)

There is moderate evidence of a statistical association between cannabis smoking and:

• Improved airway dynamics with acute use, but not with chronic use

• Higher forced vital capacity (FVC)

There is moderate evidence of a statistical association between the cessation of cannabis smoking and:

• Improvements in respiratory symptoms



Trends in fatal motor vehicle crashes before and after marijuana commercialization in CO

24

Salomonsen-Sautel, S. Drug & Alcohol Dependence, 2014


Health effects of cannabis and cannabinoids: Injury and death

There is substantial evidence of a statistical association between cannabis use and:

• Increased risk of motor vehicle crashes


• Increased risk of overdose injuries, including respiratory distress, among pediatric populations in U.S. states where cannabis is legal (9-4b)



• Pharmacotherapy

– No currently approved medication

• cannabinoid antagonist

• oral THC for withdrawal, maintenance or short-term treatment?

• cannabinoid agonist—Levin FR DAD 2011

• N-Acetylcysteine

• Behavioral

– Substance use treatment setting

• cognitive-behavioral therapy, contingency management, motivational enhancement, therapeutic living

– General medical settings

• Brief interventions

Treatment Options


Synthetic marijuana: K2, Spice, etc.

• General Information:

– Marketed as safe legal alternative to marijuana; generally smoked; very common among adolescents

• Effects:– Mild euphoria and relaxation– The ‘giggles’– Increased sensitivity to external stimuli– Frank, vivid hallucinations

• Adverse effects:– Dry mouth, palpitations, rapid HR, vomiting, agitation– Not detected in urine– May be adulterated with heavy metal residues or other

fillers including rat poison- severe bleeding (Apr 2018)


Fundamental tension

• Intoxication and withdrawal of marijuana are not fatal

• Overdose is unlikely

• Long-term, moderate use seems to be relatively frequent (compared to other drugs)

• Risk of end-organ damage appears to be lower than several other legal and illegal substances

• Ratio of medical benefit to harm may be equal or better than some controlled substances


Health effects of cannabis and cannabinoids: Therapeutic effects

There is conclusive or substantial evidence that cannabis or cannabinoids are effective:

• For the treatment of chronic pain in adults (cannabis)

• As antiemetics in the treatment of chemotherapy-induced nausea and vomiting (oral cannabinoids)

• For improving patient-reported multiple sclerosis spasticity symptoms (oral cannabinoids)

There is moderate evidence that cannabis or cannabinoids are effective for:

• Improving short-term sleep outcomes in individuals with sleep disturbance associated with obstructive sleep apnea syndrome, fibromyalgia, chronic pain, and multiple sclerosis (cannabinoids, primarily nabiximols)



Cannbinoids for medical use: Pain

Whiting PF et al. JAMA.2015;313(24):2456-2473

30% decrease in pain w cannabinoid vs placebo:

OR 1.41 (95% CI, 0.99-2.00)


Medical Marijuana and OD risk

Bachhuber MA et al. JAMA 2014


Marijuana legislation and prescription opioids

• Between 2011-2016, among Medicaid enrollees, medical marijuana laws associated with 5.88% lower opioid prescribing rates

– Adult-use marijuana laws associated with 6.38% lower opioid prescribing rates

• Between 2010-2015, among Medicare part D recipients, prescriptions filled for all opioids decreased by 2 million daily doses per year from an average of 23 million daily doses per year when a state instituted any medical cannabis law.

– Prescriptions for all opioids decreased by 3.742 million daily doses per year when medical cannabis dispensaries opened.

• Cannabis use associated with increase in nonmedical use of prescription opioids(OR 5.78, 95% CI 4.23-7.9)

– Cannabis use associated with OUD (OR 7.76, 95% CI 4.95-12.2)

Wen, H et al, JAMA Internal Medicine Apr 2018Bradford AC et al. JAMA Internal Medicine Apr 2018Hill KP et al, JAMA Internal Medicine Apr 2018Olfson M et al. Am J Psychiatry 2018


State Level Variation

• Physician certification for patients with certain qualifying diagnoses

• Patient may possess only a one month supply (varies)

– CT=2.5 oz; WA=12 oz

• Growers are certified by Department of Consumer Protection to cultivate MJ

– Application fee often prohibitive

• Pharmacists able to obtain a dispensing license from DCP

– State regulates amount of licenses


Challenges in conducting research on adverse health effects or therapeutic effects of cannabis

• Regulatory barriers, including the classification of cannabis as a Schedule I substance, impede the advancement of cannabis research

• Difficult for researchers to gain access to the quantity, quality, and type of product necessary to address research questions on health effects

• A diverse network of funders is needed to support cannabis research

• To develop conclusive evidence for the effects of cannabis use on short- and long-term health outcomes, improvements and standardization in research methodology (including those used in controlled trials and observational studies) are needed



Thank you

Questions?

Acknowledgements: several slides adapted from Dr. William Becker (Yale), Dr. Hilary Kunins (NY DPH), Dr. Jeffrety Hunt (Brown), Dr. Zoe Weinstein (BU)


Extra Slides


Current State of the Union

States with Recreational Laws:

WashingtonOregonCaliforniaNevadaAlaskaColoradoMassachusettsMaineVermont+ Washington D.C.

Guam, PR

17 States with CBD specific

laws


Interactive teaching scenario: Morning report/role play

• Set up a “spicy,” public health debate regarding legalization of recreational marijuana using the following citation as a spring board for discussion:

Kilmer B. Recreational Cannabis — Minimizing the Health Risks

from Legalization. Perspective. NEJM. February 23, 2017

• Assign report participants to one of two groups:

– Recreational marijuana SHOULD be legalized in all states nationwide• Citing adverse effects of criminalization and potential for increasing state budgets through taxation,

potential impact on opioid epidemic

– Recreational marijuana SHOULD NOT be legalized in all states nationwide• Citing current research on adverse health effects and natural experiment data from states that have

already legalized recreational marijuana

• All arguments need to be evidence-based and factual


Other cognitive effects of marijuana

• In a large study of 5115 adults at 18-30yo at baseline followed up for 25 years

• Current use of marijuana associated with worse verbal memory and processing speed

• Cumulative lifetime exposure was associated with worse performance in verbal memory, processing speed and executive function

• For each 5 years of past exposure, verbal memory was 0.13 standardized units lower (95% CI, −0.24 to −0.02; P = .02)

– corresponds to remembering 1 word less from a list of 15, for every 5 years of use.

Auer R et al. JAMA Intern Med. 2016;176(3):352-361


Auer R et al. JAMA Intern Med. 2016;176(3):352-361

Association between lifetime marijuana use and cognitive

function in middle age: The CARDIA Study


Genetic variation influences harmful effects of marijuana

BIOL PSYCHIATRY 2012;72:811–816


Odds of Adverse Events

Whiting PF et al. JAMA.

2015;313(24):2456-2473


Health effects of cannabis and cannabinoids: Other effects

There is substantial evidence of a statistical association between maternal cannabis smoking and:

• Lower birth weight of the offspring

There is limited evidence of a statistical association between maternal cannabis smoking and:

• Pregnancy complications for the mother

• Admission of the infant to the neonatal intensive care unit (NICU)

There is moderate evidence of no statistical association between cannabis use and:

• Incidence of lung cancer (cannabis smoking)

• Incidence of head and neck cancersReport of National Academies of Science, Engineering and Medicine. Health Effects of Cannabis and Cannabinoids. 2017

marijuana: clearing the smoke on clinical and policy issues · 2018-07-23 · disorder for...

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